title: Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC-PGL syndromes: a clinicopathological and molecular analysis.
abstract: OBJECTIVE
  Although the succinate dehydrogenase (SDH)-related tumor spectrum has been recently expanded, there are only rare reports of non-pheochromocytoma/paraganglioma tumors in SDHx-mutated patients. Therefore, questions still remain unresolved concerning the aforementioned tumors with regard to their pathogenesis, clinicopathological phenotype, and even causal relatedness to SDHx mutations. Absence of SDHB expression in tumors derived from tissues susceptible to SDH deficiency is not fully elucidated.
  
  
  METHODS
  Three unrelated SDHD patients, two with pituitary adenoma (PA) and one with papillary thyroid carcinoma (PTC), and three SDHB patients affected by renal cell carcinomas (RCCs) were identified from four European centers. SDHA/SDHB immunohistochemistry (IHC), SDHx mutation analysis, and loss of heterozygosity analysis of the involved SDHx gene were performed on all tumors. A cohort of 348 tumors of unknown SDHx mutational status, including renal tumors, PTCs, PAs, neuroblastic tumors, seminomas, and adenomatoid tumors, was investigated by SDHB IHC.
  
  
  RESULTS
  Of the six index patients, all RCCs and one PA displayed SDHB immunonegativity in contrast to the other PA and PTC. All immunonegative tumors demonstrated loss of the WT allele, indicating bi-allelic inactivation of the germline mutated gene. Of 348 tumors, one clear cell RCC exhibited partial loss of SDHB expression.
  
  
  CONCLUSIONS
  These findings strengthen the etiological association of SDHx genes with pituitary neoplasia and provide evidence against a link between PTC and SDHx mutations. Somatic deletions seem to constitute the second hit in SDHB-related renal neoplasia, while SDHx alterations do not appear to be primary drivers in sporadic tumorigenesis from tissues affected by SDH deficiency.
authors.affiliation: Department of Pathology, Josephine Nefkens Institute, Erasmus MC, University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Papathomas
authors.forename: Jose
authors.initials: J
authors.lastname: Gaal
authors.forename: Eleonora P M
authors.initials: EP
authors.lastname: Corssmit
authors.forename: Lindsey
authors.initials: L
authors.lastname: Oudijk
authors.forename: Esther
authors.initials: E
authors.lastname: Korpershoek
authors.forename: Ketil
authors.initials: K
authors.lastname: Heimdal
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bayley
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
authors.forename: Marieke
authors.initials: M
authors.lastname: van Dooren
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Papaspyrou
authors.forename: Thomas
authors.initials: T
authors.lastname: Schreiner
authors.forename: Torsten
authors.initials: T
authors.lastname: Hansen
authors.forename: Per Arne
authors.initials: PA
authors.lastname: Andresen
authors.forename: David F
authors.initials: DF
authors.lastname: Restuccia
authors.forename: Ingrid
authors.initials: I
authors.lastname: van Kessel
authors.forename: Geert J L H
authors.initials: GJ
authors.lastname: van Leenders
authors.forename: Johan M
authors.initials: JM
authors.lastname: Kros
authors.forename: Leendert H J
authors.initials: LH
authors.lastname: Looijenga
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Hofland
authors.forename: Wolf
authors.initials: W
authors.lastname: Mann
authors.forename: Francien H
authors.initials: FH
authors.lastname: van Nederveen
authors.forename: Ozgur
authors.initials: O
authors.lastname: Mete
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Asa
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
authors.forename: Winand N M
authors.initials: WN
authors.lastname: Dinjens
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002291:Carcinoma, Papillary / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005091:Exons; D005260:Female; D017353:Gene Deletion; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013385:Succinate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D009363:Neoplasm Proteins; C491545:SDHD protein, human; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase